Hepatitis D virus (HDV) - the "D" is for delta - is a viral enigma that doesn't act like a normal virus. It is helpless - that is, it can't infect a cell - without its viral accomplice, the hepatitis B virus (HBV), and makes infection with HBV worse.

Delta virus can only cause illness in those already infected with HBV, said Timothy Block, Ph.D., director and professor of the Drexel University Institute for Biotechnology and Virology Research.

"It can take quiescent HBV and turn it into an acute, lethal viral infection," Block said. "Liver disease - cirrhosis, liver failure - that might take decades to develop or could only take a year or two. Delta virus converts HBV infection into an emergency situation."

"It's one of the most severe forms of human viral hepatitis," said Jeffrey Glenn, M.D., Ph.D., assistant professor of medicine at Stanford University School of Medicine.

"Delta virus is a parasite of HBV because it encodes its own genome and coat-like protein but it doesn't make its own envelope protein," Glenn explained. "It steals that from HBV. It needs the B envelope protein to make its own, and this provides a means to infect new cells and subsequently make a fully formed viral particle to get out of those cells to infect others."

Individuals can acquire delta virus two ways: Either after infection with HBV, which is called a "superinfection" and more likely to stay chronic, or a "co-infection", which entails becoming infected with both viruses at the same time. In the latter, acute infections are more severe and increase the likelihood of developing liver disease much more quickly.

Perhaps 10 to 15 million worldwide are infected, though fewer than 100,000 in the U.S. have the virus. It is concentrated in particular regions worldwide. Mediterranean areas - southern Italy and southern Greece, for example - have larger than usual numbers of affected individuals, and in Turkey it is endemic.

Some believe its incidence is declining. "As a disease it's disappearing, probably a result of the HBV vaccine and a reduced number of HBV carriers," said John Taylor, Ph.D., senior member at Fox Chase Cancer Center.

Because HDV is not a huge problem in the U.S., it flies under the radar screen of public awareness. Screening for HDV is not routinely ordered; however, infection with delta virus should always be considered when a patient with chronic liver disease suddenly gets worse, said Taylor.

Researchers have been frustrated in their attempts to develop effective treatments against HDV. Newer antiviral drugs that keep down levels of HBV DNA don't do much against delta virus because they don't affect the HBV envelope protein. The antiviral drug lamivudine, for example, reduces HBV DNA yet doesn't touch its envelope protein. And interferon hasn't helped much thus far.

Current Research Directions

With research there is always hope. Glenn and his co-workers have discovered that the delta antigen is modified by a specific lipid called a prenylipid in a process known as prenylation, which is necessary to make a delta virus particle.

"Preventing this means no particles are made," he said "A drug that could prevent prenylation of delta antigen could be a practical therapy."

His research team is looking at the effectiveness of potential drugs in progressively advanced models of delta infection. More recently, they established a mouse model of delta virus infection and completely cleared the virus from the blood of mice using these drugs.

"We've been working on these for the last decade and think they hold much promise," Glenn said. "We're hoping sometime in the next year to do the first human trial of a drug specifically targeting this process."

Fox Chase's Taylor said that understanding how delta virus infects new cells could provide keys to how HBV enters new cells. "The delta studies have come a long way, but we need to understand more about its behavior before we can find effective drugs."

FAST FACTS ABOUT HEPATITIS D

• Delta hepatitis is one of the most severe forms of viral hepatitis.
• It is an incomplete viral particle that was discovered in 1997.
• Approximately 15 million people are infected with HDV worldwide.
• In the U.S., an estimated 6,000-13,000 people suffer acute HDV infection each year; 30,000 suffer from chronic HDV; and 1,000 Americans die from HDV-related diseases annually.
• It is transmitted by blood from people already infected with hepatitis B.
• Preventing hepatitis B, especially vaccination, will prevent HDV.
• There is no effective treatment for HDV.